The importance of the vitamin D in the biological systems of higher animals has been recognized since its discovery by Mellanby in 1920 (Mellanby, E. (1921) Spec. Rep. Ser. Med. Res. Council (GB) SRS 61:4). It was in the interval of 1920-1930 that vitamin D officially became classified as a "vitamin" that was essential for the normal development of the skeleton and maintenance of calcium and phosphorous homeostasis.
Vitamin D.sub.2 (ergocalciferol) and vitamin D.sub.3 (cholecalciferol) are the two important nutritional forms of vitamin D out of all the known forms of vitamin D. Provitamin D.sub.3 (7-dehydrocholesterol) exists in the skin of animals, while provitamin D.sub.2 (ergosterol) exists in plants and in many lower organisms, such as fungi and yeasts. Provitamins D.sub.2 and D.sub.3 are converted into their corresponding vitamins D.sub.2 and D.sub.3 when exposed to UV radiation. The two vitamins differ only in the structure of their side chains (the side chain of vitamin D.sub.2 has an extra methyl group at C-24 and a double bond between C-22 and C-23 when compared to the side chain of vitamin D.sub.3). Historically, vitamin D.sub.2 became important medicine as it was the first synthetic vitamin D preparation available for the treatment of rickets, and it is still being widely used to satisfy both therapeutic and nutritional needs of man and other commercially important mammals.
It is the generally believed that the further metabolic pathways of vitamin D.sub.2 are similar to those of vitamin D.sub.3 (Norman, A. et al., (1982) Endocr. Rev. 3:331-336). Vitamin D.sub.2, like vitamin D.sub.3, undergoes hydroxylations at C-25 in liver and at C-1 in kidney to form 1,25(OH).sub.2 D.sub.2, the hormonally active form of vitamin D.sub.2 (Jones, G. et al., (1975) Biochemistry 14:1250-1256). During the past decade, the pathways of side-chain metabolism of vitamin D.sub.3 metabolites [25-OH-D.sub.3 and 1,25(OH).sub.2 D.sub.3 ] have been studied extensively. It is now apparent that the side chains of both 25-OH-D.sub.3 and 1,25-(OH).sub.2 D.sub.3 undergo analogous metabolic alterations resulting in the formation of many relatively inactive metabolites, and this subject has been extensively studied in several laboratories.
Given the pluripotent activities of vitamin D and its metabolites, much attention has focused on the development of synthetic analogs of these compounds. However, clinical applications of vitamin D and its structural analogs have been limited by the undesired side effects elicited by these compounds after administration to a subject, such as the deregulation of calcium and phosphorous homeostasis in vivo that results in hypercalcemia.